Title | Glucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Rollins DA, Kharlyngdoh JB, Coppo M, Tharmalingam B, Mimouna S, Guo Z, Sacta MA, Pufall MA, Fisher RP, Hu X, Chinenov Y, Rogatsky I |
Journal | Nat Commun |
Volume | 8 |
Issue | 1 |
Pagination | 1739 |
Date Published | 2017 Nov 23 |
ISSN | 2041-1723 |
Abstract | The glucocorticoid (GC) receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein-1 (GRIP1) is a GR corepressor in macrophages, however, whether GRIP1 mediates GR-activated transcription, and what dictates its coactivator versus corepressor properties is unknown. Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator. Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. Consistently, phospho-GRIP1 and CDK9 are not detected at GR transrepression sites near pro-inflammatory genes. Thus, GR restricts actions of its own coregulator via CDK9-mediated phosphorylation to a subset of anti-inflammatory genes. |
DOI | 10.1038/s41467-017-01569-2 |
Alternate Journal | Nat Commun |
PubMed ID | 29170386 |
PubMed Central ID | PMC5700924 |
Grant List | R00 CA149088 / CA / NCI NIH HHS / United States P30 CA086862 / CA / NCI NIH HHS / United States R01 DK099087 / DK / NIDDK NIH HHS / United States T32 AR007281 / AR / NIAMS NIH HHS / United States R01 GM104291 / GM / NIGMS NIH HHS / United States K99 CA149088 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:10pm